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SOMAVERT (pegvisomant for injection)

Health Professional Information

SUMMARY PRODUCT INFORMATION

Route of Administration

Dosage Form / Strength

Clinically Relevant Nonmedicinal Ingredients

Subcutaneous injection

lyophilized powder, 10, 15, 20, 25 and 30 mg per vial in package that also includes diluent (Sterile Water for Injection, Ph. Eur.) in a vial or pre-filled syringe

None

For a complete listing see Dosage Forms, Composition and Packaging section.

Indications And Clinical Use

SOMAVERT (pegvisomant for injection) is indicated for the treatment of acromegaly in patients who have had an inadequate response to surgery, and/or radiation therapy or for whom these therapies are not appropriate. The goal of treatment is to normalize serum insulin-like growth factor-I (IGF-I) levels and to improve clinical signs and symptoms. 

Geriatrics (> 65 years of age): There is limited information in patients over 65 years of age (see WARNINGS AND PRECAUTIONS, Special Populations, Geriatrics).

Pediatrics (< 18 years of age): The safety and effectiveness of SOMAVERT in pediatric patients have not been established.

Contraindications

SOMAVERT (pegvisomant for injection) is contraindicated in patients with a history of hypersensitivity to any of its components. The stoppers on the vial of SOMAVERT and the vial of diluent are latex free.

Warnings And Precautions

General

In clinical studies, patients on opioids often needed higher serum pegvisomant concentrations to achieve appropriate IGF-I suppression compared with patients not receiving opioids (see DRUG INTERACTIONS, Drug-Drug Interactions and DOSAGE AND ADMINISTRATION, Recommended Dose and Dosage Adjustment).

Tumor Growth

Tumors that secrete growth hormone (GH) may expand and cause serious complications. Therefore, all patients with these tumors, including those who are receiving SOMAVERT (pegvisomant for injection), should be carefully monitored with periodic imaging scans of the sella turcica. During clinical studies of SOMAVERT, two patients manifested progressive tumor growth. Both patients had, at baseline, large globular tumors impinging on the optic chiasm, which had been relatively resistant to previous anti-acromegalic therapies. Overall, mean tumor size was unchanged during the course of treatment with SOMAVERT in the clinical studies.

Information for Patients

Patients and any other persons who may administer SOMAVERT should be carefully instructed by a health care professional on how to properly reconstitute and inject the product (see PART III: CONSUMER INFORMATION). No studies on the effect on the ability to drive and use machines have been performed.

Patients should be informed about the need for serial monitoring of liver enzyme tests, and told to discontinue therapy and contact their physician if they become jaundiced immediately. In addition, patients should be made aware that serial IGF-I levels will need to be obtained to allow their physician to properly adjust the dose of SOMAVERT.

Endocrine and Metabolism

Glucose Metabolism

GH opposes the effects of insulin on carbohydrate metabolism by decreasing insulin sensitivity; thus, glucose tolerance may increase in some patients treated with SOMAVERT. Although no clinically relevant hypoglycemia was observed during clinical trials among acromegalic patients with diabetes treated with SOMAVERT, these patients should be carefully monitored and doses of anti-diabetic drugs reduced as necessary (see DRUG INTERACTIONS, Drug-Drug Interactions and DOSAGE AND ADMINISTRATION, Recommended Dose and Dosage Adjustment).

GH Deficiency

SOMAVERT is a potent antagonist of GH action. A state of functional GH deficiency may result from administration of SOMAVERT, despite the presence of elevated serum GH levels. During treatment with SOMAVERT, patients should be carefully observed for clinical signs and symptoms of a GH-deficient state. Dose adjustments of SOMAVERT should be made to maintain serum IGF-I concentrations within the age-adjusted normal range.

Hepatic/Biliary/Pancreatic

Liver Tests (LTs)

Elevations of serum concentrations of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) greater than 10 times the upper limit of normal (ULN) were reported in two patients (0.8%) treated with SOMAVERT during pre-marketing clinical studies. One patient was rechallenged with SOMAVERT, and the recurrence of elevated transaminase levels suggested a probable causal relationship between administration of the drug and the elevation in liver enzymes. A liver biopsy performed on the second patient was consistent with chronic hepatitis of unknown etiology. In both patients, the transaminase elevations normalized after discontinuation of the drug.

During the pre-marketing clinical studies, the incidence of elevations in ALT greater than 3 times but less than or equal to 10 times the ULN in patients treated with SOMAVERT and placebo were 1.2% and 2.1%, respectively.

Elevations in ALT and AST levels were not associated with increased levels of serum total bilirubin (TBIL) and alkaline phosphatase (ALP), with the exception of two patients with minimal associated increases in ALP levels (i.e., less than 3 times ULN). The transaminase elevations did not appear to be related to the dose of SOMAVERT administered, generally occurred within 4 to 12 weeks of initiation of therapy, and were not associated with any identifiable biochemical, phenotypic, or genetic predictors.

In a global post-marketing combination study with a somatostatin analogue, one out of 25 patients in the pegvisomant group and 1 out of 27 in the octreotide acetate group had transaminases greater than three or more times the upper limit of normal (ULN). Three patients out of 26 (approximately 10%) treated with the combination were found to have serum concentrations of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ranging from 13 to 45 times the ULN within 3 months of starting this treatment. Two of these patients received supratherapeutic doses of octreotide acetate (30 mg every 2 weeks) combined with a normal dose of SOMAVERT (10 mg daily). All three patients completely recovered after discontinuation of treatment. The safety and efficacy of pegvisomant in combination with other medicinal products, including somatostatin analogues, in the treatment of acromegaly have not been established and, therefore, the combination of somatostatin analogues with pegvisomant is not recommended.

Baseline serum ALT, AST, TBIL, and ALP levels should be obtained prior to initiating therapy with SOMAVERT. Table 1 lists recommendations regarding initiation of treatment with SOMAVERT, based on the results of these liver tests (LTs).

If a patient develops LT elevations, or any other signs or symptoms of liver dysfunction while receiving SOMAVERT, the following patient management is recommended (Table 2).

Table 1. Initiation of Treatment with SOMAVERT Based on Results of Liver Tests

Baseline LT Levels

Recommendations

Normal

May treat with SOMAVERT. Monitor LTs at monthly intervals during the first 6 months of treatment, quarterly for the next 6 months, and then biannually for the next year.

Elevated, but less than or

equal to 3 times ULN

May treat with SOMAVERT; however, monitor LTs monthly for at least one year after initiation of therapy and then biannually for the next year.

Greater than 3 times ULN

Do not treat with SOMAVERT until a comprehensive workup establishes the cause of the patient’s liver dysfunction. Determine if cholelithiasis or choledocholithiasis is present, particularly in patients with a history of prior therapy with somatostatin analogs. Based on the workup, consider initiation of therapy with SOMAVERT. If the decision is to treat, LTs and clinical symptoms should be monitored very closely.

Table 2. Continuation of Treatment with SOMAVERT Based on Results of Liver Tests

LT Levels and Clinical Signs/Symptoms

Recommendations

Greater than or equal to 3 but less

than 5 times ULN (without signs/

symptoms of hepatitis or other liver injury, or increase in serum TBIL)

May continue therapy with SOMAVERT. However, monitor LTs weekly to determine if further increases occur (see below). In addition, perform a comprehensive hepatic workup to discern if an alternative cause of liver dysfunction is present.

At least 5 times ULN, or

transaminase elevations at least

3 times ULN associated with any

increase in serum TBIL (with or

without signs/symptoms of

hepatitis or other liver injury)

Discontinue SOMAVERT immediately. Perform a comprehensive hepatic workup, including serial LTs, to determine if and when serum levels return to normal. If LTs normalize (regardless of whether an alternative cause of the liver dysfunction is discovered), consider cautious reinitiation of therapy with SOMAVERT, with frequent LT monitoring.

Signs or symptoms suggestive of

hepatitis or other liver injury

(e.g., jaundice, bilirubinuria,

fatigue, nausea, vomiting,

right upper quadrant pain,

ascites, unexplained edema,

easy bruisability)

Discontinue SOMAVERT immediately.

Immediately perform a comprehensive hepatic workup. If liver injury is confirmed, the drug should be discontinued permanently.

Immune

Immunogenicity

In pre-marketing clinical studies, approximately 17% of the patients had low titer, non-neutralizing anti-GH antibodies. These antibodies do not appear to have clinical significance. An assay for anti-pegvisomant antibodies in a patient receiving SOMAVERT is not commercially available.

Systemic hypersensitivity

Systemic hypersensitivity reactions including anaphylactic/anaphylactoid reactions, laryngospasm, angioedema, generalized skin reactions have been reported with SOMAVERT. Caution and close monitoring should be exercised when re-initiating SOMAVERT therapy (see ADVERSE REACTIONS, Immune system disorders).

Cross-Reactivity with GH Assays

SOMAVERT has significant structural similarity to growth hormone (GH) which causes it to cross-react in commercially available GH assays. Since serum concentrations of therapeutically effective doses of SOMAVERT are generally 100 to 1000 times higher than the actual serum GH concentrations seen in patients with acromegaly, measurements of serum GH concentrations will appear falsely elevated.

Lipohypertrophy

There have been cases of lipohypertrophy in patients treated with SOMAVERT. In a double-blind, 12-week, placebo-controlled study, there was one case (1.3%) of injection site lipohypertrophy reported in a subject receiving 10 mg/day. The subject recovered while on treatment. Among two open-label trials (with a total of 147 patients), there were two subjects, both receiving 10 mg/day, who developed lipohypertrophy. One case recovered while on treatment, and one case resulted in a discontinuation of treatment. Injection sites should be rotated daily to help prevent lipohypertrophy (different area than the last injection).

Special Populations

Pregnant Women:

There are no adequate and well-controlled studies in pregnant women. SOMAVERT should be used during pregnancy only if the potential benefit justifies the potential risk to the patient.

Nursing Women:

It is not known whether pegvisomant is excreted in human milk. Because many drugs are excreted in human milk, caution should be exercised when SOMAVERT is administered to a nursing woman.

Pediatrics (< 18 years of age):

The safety and effectiveness of SOMAVERT in pediatric patients have not been established.

Geriatrics (> 65 years of age):

Clinical studies of SOMAVERT did not include sufficient numbers of subjects aged 65 and over to determine whether these subjects respond differently from younger subjects. In general, dose selection for an elderly patient should be cautious, usually starting at the low end of the dosing range, reflecting the greater frequency of decreased hepatic, renal, or cardiac function, and of concomitant disease or other drug therapy.

Monitoring and Laboratory Tests

Liver Tests

Recommendations for monitoring liver function are stated above (see WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic, Liver Tests [LTs]).

IGF-I Levels

Treatment with SOMAVERT should be evaluated by monitoring serum IGF-I concentrations four to six weeks after therapy is initiated or any dose adjustments are made, and at least every six months after IGF-I levels have normalized. The goals of treatment should be to maintain a patient’s serum IGF-I concentration within the age-adjusted normal range and to control the signs and symptoms of acromegaly.

GH Levels

Pegvisomant interferes with the measurement of serum GH concentrations by commercially available GH assays (see DRUG INTERACTIONS, Drug-Laboratory Interactions). Furthermore, even when accurately determined, GH levels usually increase during therapy with SOMAVERT. Therefore, treatment with SOMAVERT should not be monitored or adjusted based on serum GH concentrations.

Adverse Reactions

Adverse Drug Reaction Overview

Safety was evaluated in a randomized, multicenter, placebo-controlled, 12‑week study, of patients treated with 10 mg/day (n=26), 15 mg/day (n=26), or 20 mg/day (n=28) of SOMAVERT (pegvisomant for injection) or placebo (n=32).

Table 3 shows the incidence of treatment-emergent adverse events reported in at least two patients treated with SOMAVERT and at frequencies greater than placebo during the 12-week, placebo-controlled study. The majority of reported adverse events were of mild to moderate intensity and limited duration. Adverse events did not appear to be dose dependent.

Clinical Trial Adverse Drug Reactions

Because clinical trials are conducted under very specific conditions the adverse reaction rates observed in the clinical trials may not reflect the rates observed in practice and should not be compared to the rates in the clinical trials of another drug. Adverse drug reaction information from clinical trials is useful for identifying drug-related adverse events and for approximating rates.

Table 3. Number of Patients with Acromegaly (Incidence) Reporting Adverse Events in a 12-week Placebo-controlled Study with SOMAVERT1
1

Table includes only those events that were reported in at least 2 patients and at a higher incidence in patients treated with SOMAVERT than in patients treated with placebo.

The 6 events coded as "infection" in the group treated with SOMAVERT 10 mg were reported as cold symptoms (3), upper respiratory infection (1), blister (1), and ear infection (1).The 2 events in the placebo group were reported as cold symptoms (1) and chest infection (1).

*

including injection site hypersensitivity and/or injection site hypertrophy (e.g, lipohypertrophy)

Event

SOMAVERT

Placebo

n=32

10 mg/day

n=26

15 mg/day

n=26

20 mg/day

n=28

Body as a Whole

Infection

6 (23%)

0

0

2 (6%)

Pain

2 (8%)

1 (4%)

4 (14%)

2 (6%)

Injection site reaction*

2 (8%)

1(4%)

3 (11%)

0

Injury

2 (8%)

1(4%)

0

1 (3%)

Back pain

2 (8%)

0

1 (4%)

1 (3%)

Influenza

1 (4%)

3 (12%)

2 (7%)

0

Chest pain

1 (4%)

2 (8%)

0

0

Digestive

Liver function test Abnormal

3 (12%)

1 (4%)

1 (4%)

1 (3%)

Diarrhea

1 (4%)

0

4 (14%)

1 (3%)

Nausea

0

2 (8%)

4 (14%)

1 (3%)

Nervous

Dizziness

2 (8%)

1 (4%)

1 (4%)

2 (6%)

Paresthesia

0

0

2 (7%)

2 (6%)

Metabolic and nutritional disorders

Edema peripheral

2 (8%)

0

1 (4%)

0

Cardiovascular

Hypertension

0

2 (8%)

0

0

Respiratory

Sinusitis

2 (8%)

0

1 (4%)

1 (3%)

Nine acromegalic patients (5.6%) withdrew from pre-marketing clinical studies because of adverse events, including two patients with marked transaminase elevations (WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic, Liver Tests [LTs]), one patient with lipohypertrophy at the injection sites, and one patient with substantial weight gain.

Abnormal Hematologic and Clinical Chemistry Findings

Laboratory Changes

Elevations of serum concentrations of ALT and AST greater than ten times the ULN were reported in two subjects (0.8%) exposed to SOMAVERT in pre-marketing clinical studies (see WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic, Liver Tests [LTs]).

Immunogenicity

In pre-marketing clinical studies, approximately 17% of the patients had low titer, non-neutralizing anti-GH antibodies. These antibodies do not appear to have clinical significance. An assay for anti-pegvisomant antibodies in a patient receiving SOMAVERT is not commercially available.

Post-Marketing Adverse Drug Reactions

The following adverse reactions have been identified during post-approval use of SOMAVERT. Because these reactions are reported voluntarily from a population of uncertain size, it is not possible to reliably estimate their frequency.

Immune system disorders

Systemic hypersensitivity reactions including anaphylactic/anaphylactoid reactions, laryngospasm, angioedema, generalized skin reactions (rash, erythema, pruritus, urticaria) have been reported with SOMAVERT (see WARNINGS AND PRECAUTIONS). Some patients required hospitalization. Upon re-administration, symptoms did not re-occur in all patients.

Registry of Patients with Acromegaly Treated with SOMAVERT

ACROSTUDY is an international observational registry that captures long term safety data in patients with acromegaly treated with SOMAVERT, as used in clinical practice. Treatment dose and schedule were at the discretion of each treating physician. Although safety monitoring as per the recommended schedule was mandatory, not all assessments were performed at all time points for every patient. Because of this, comparison of rates of adverse events to those in the original clinical trial is not appropriate. In an interim report, there were 1288 patients enrolled (mean duration of treatment 3.7 years).

At the start of SOMAVERT treatment 648 patients were on SOMAVERT monotherapy for acromegaly. Of the 454 patients who had a normal AST and ALT at baseline, 4 patients had elevated tests >3 times ULN, two of whom had elevated tests >5 times ULN.

Lipohypertrophy was reported in 6 (0.5%) patients.

MRIs were compared to any previous ones, and a change in tumor volume was reported as significant locally only if the diameter increased by more than 3 mm for microadenomas or volume increased by more than 20% for macroadenomas. All MRI changes considered significant at the local reading were reanalyzed centrally. Of the 747 patients who had a MRI reported at baseline and at least once during follow up in the study, 51 (7%) were reported to have an increase by local MRI. Of these, 16 patients (2%) had confirmation of this increase, 6 patients had a decrease, 12 had “no change”; there was 1 with insufficient data and 16 patients did not have a central MRI reading.

Drug Interactions

Drug-Drug Interactions

Acromegalic patients with diabetes mellitus being treated with insulin and/or oral hypoglycemic agents may require dose reductions of these therapeutic agents after the initiation of therapy with SOMAVERT (pegvisomant for injection) (see WARNINGS AND PRECAUTIONS, Endocrine and Metabolism, Glucose Metabolism and DOSAGE AND ADMINISTRATION, Recommended Dose and Dosage Adjustment).

Some patients concomitantly receiving opioids required higher serum concentrations of pegvisomant to achieve appropriate IGF-I suppression as compared to patients not receiving opioids, suggesting opioids may confer a resistance to the clinical effects of pegvisomant. The mechanism of action and their clinical relevance is unclear (or unknown) (see WARNINGS AND PRECAUTIONS, General and DOSAGE AND ADMINISTRATION, Recommended Dose and Dosage Adjustment).

Pegvisomant in combination with Somatostatin analogues

Hepatic enzyme elevations (greater than 10 times upper limit of normal [ULN]) have been reported in patients treated with the combination of SOMAVERT and octreotide acetate particularly when higher than recommended doses of octreotide acetate were used. The safety and efficacy of pegvisomant in combination with other medicinal products, including somatostatin analogues, in the treatment of acromegaly have not been established and, therefore, the combination of somatostatin analogues with pegvisomant is not recommended (see WARNINGS AND PRECAUTIONS, Hepatic/Biliary/Pancreatic).

Drug-Laboratory Interactions

Pegvisomant has significant structural similarity to GH, which causes it to cross-react in commercially available GH assays. Because serum concentrations of pegvisomant at therapeutically effective doses are generally 100 to 1000 times higher than endogenous serum GH levels seen in patients with acromegaly, commercially available GH assays will overestimate true GH levels. Treatment with SOMAVERT should therefore not be monitored or adjusted based on serum GH concentrations reported from these assays. Instead, monitoring and dose adjustments should only be based on serum IGF-I levels.

Dosage And Administration

Recommended Dose and Dosage Adjustment

The recommended loading dose of pegvisomant is 40 mg given subcutaneously (SC), under the supervision of a healthcare provider. Proper training in SC injection technique should be provided to patients or their caregivers so that patients can receive once-daily SC injections. On the next day following the loading dose, patients or their caregivers should be instructed to begin daily injections of pegvisomant 10 mg SC.

The pegvisomant dose should be titrated to normalize serum IGF-I concentrations, and serum IGF-I concentrations should be measured every 4-6 weeks. The dose should not be based on GH concentrations. It is unknown whether patients who remain symptomatic while achieving normalized IGF-I concentrations would benefit from increased pegvisomant dosage.

  • The dose should be increased by 5 mg increments every 4-6 weeks if IGF-I concentrations are elevated.

  • The dose should be decreased by 5 mg decrements every 4-6 weeks if IGF-I concentrations are below the normal range.

  • IGF-I levels should also be monitored when a pegvisomant dose given in multiple injections is converted to a single daily injection.

The recommended dose range is between 10 to 30 mg SC once daily, and the maximum daily dose is 30 mg SC once daily.

Acromegalic patients with diabetes mellitus being treated with insulin and/or oral hypoglycemic agents may require dose reductions of these therapeutic agents after the initiation of therapy with SOMAVERT (pegvisomant for injection) (see WARNINGS AND PRECAUTIONS, Endocrine and Metabolism, Glucose Metabolism and DRUG INTERACTIONS, Drug-Drug Interactions).

Some patients concomitantly receiving opioids may require higher serum concentrations of pegvisomant to achieve appropriate IGF-I suppression (see WARNINGS AND PRECAUTIONS, General and DRUG INTERACTIONS, Drug-Drug Interactions).

Administration

SOMAVERT is supplied as a lyophilized powder in a vial. Each vial of SOMAVERT should be reconstituted with 1 mL of the diluent (Sterile Water for Injection, Ph. Eur) provided in a vial or in a pre-filled syringe that is included in the package. Detailed instructions regarding reconstitution and administration are included in the package of SOMAVERT and should be closely followed.

Diluent vial presentation:

To prepare the solution, withdraw 1 mL of Sterile Water for Injection, Ph. Eur. from the diluent vial and inject it into the vial of SOMAVERT, aiming the stream of liquid against the glass wall. Hold the vial between the palms of both hands and gently roll it to dissolve the powder. DO NOT SHAKE THE VIAL, as this may cause denaturation of pegvisomant.

Diluent Pre-filled syringe presentation:

To prepare the solution, inject the diluent (Sterile Water for Injection, Ph. Eur.) from the pre-filled syringe into the vial of SOMAVERT, aiming the stream of liquid against the glass wall. Hold the vial between the palms of both hands and gently roll it to dissolve the powder. DO NOT SHAKE THE VIAL, as this may cause denaturation of pegvisomant.

After reconstitution, each vial of SOMAVERT contains 10, 15, 20, 25 or 30 mg of pegvisomant protein in 1 mL of solution. Parenteral drug products should be inspected visually for particulate matter and discoloration prior to administration. The solution should be clear after reconstitution. If the solution is cloudy, do not inject it. Only one dose should be administered from each vial. SOMAVERT should be administered within three hours after reconstitution. The site of injection should be rotated daily to help prevent lipohypertrophy.

Reconstitution:
Parenteral Products:

*
25 and 30 mg are only available in the 8 mL vial size

Vial Size

Volume of Diluent to be Added to Vial

Approximate Available Volume of diluent

Nominal Concentration per mL

6 mL or 8 mL

1 mL of Sterile Water for Injection, Ph. Eur

8 mL (vial)

1 mL (pre-filled syringe)

10, 15, 20, 25* or 30* mg of pegvisomant protein in 1 mL of solution

Overdosage

For management of a suspected drug overdose, contact your regional Poison Control Centre.

There was one reported incident of acute overdosage with SOMAVERT (pegvisomant for injection) during pre-marketing clinical studies in which a patient self-administered 80 mg/day for seven days. The patient experienced a slight increase in fatigue, had no other complaints, and demonstrated no significant clinical laboratory abnormalities.

In cases of overdose, administration of SOMAVERT should be discontinued and not resumed until IGF-I levels return to within or above the normal range.

Action And Clinical Pharmacology

Pharmacodynamics

SOMAVERT (pegvisomant for injection) contains pegvisomant for injection, an analog of human growth hormone (GH) that has been structurally altered to act as a GH receptor antagonist.

Pegvisomant selectively binds to GH receptors on cell surfaces, where it blocks the binding of endogenous GH, and thus interferes with GH signal transduction. Pegvisomant is highly selective for the GH receptor, and does not cross-react with other cytokine receptors, including prolactin.  Inhibition of GH action results in decreased serum concentrations of insulin-like growth factor-I (IGF-I), as well as other GH-responsive serum proteins, including IGFBP-3 (IGF binding protein-3), and the acid-labile subunit (ALS).

Pharmacokinetics

Absorption:  Following subcutaneous administration, peak serum pegvisomant concentrations are not generally attained until 33 to 77 hours after administration.  The mean extent of absorption of a 20-mg subcutaneous dose was 57%, relative to a 10-mg intravenous dose.

Distribution:  The mean apparent volume of distribution of pegvisomant is 7 L (12% coefficient of variation), suggesting that pegvisomant does not distribute extensively into tissues. Proportional increases in Cmax and AUC are not observed when pegvisomant is given in single, escalating doses; however, approximate dose linear pharmacokinetics are observed at steady state following multiple doses. Mean ± SD serum pegvisomant concentrations after long term therapy with daily doses of 10, 15, and 20 mg were 9300 ± 6300; 14,300 ± 7500; and 18,100 ± 10,100 ng/mL, respectively.

Studies in rats show that radiolabeled pegvisomant does not cross the blood-brain barrier.

Metabolism and Excretion:  The pegvisomant molecule contains covalently bound polyethylene glycol polymers in order to reduce the clearance rate. The mean total body systemic clearance of pegvisomant following multiple doses is estimated to be 28 mL/h (95% CI: 23.8, 32.4 mL/h) for subcutaneous doses ranging from 10 to 20 mg/day. Clearance of pegvisomant was found to increase by 0.6 mL/h for each kilogram of body weight above 94 kg. Pegvisomant had a mean serum half-life of 138 ± 68 hours following a 20 mg subcutaneous dose. Less than 1% of administered drug is recovered in the urine over 96 hours, suggesting that renal excretion is not the primary route of elimination. The elimination route of pegvisomant has not been studied in humans.

The relative bioavailability of 1 x 30 mg pegvisomant was compared to 2 x 15 mg pegvisomant in a single dose study. The AUCinf and Cmax of pegvisomant when administered as one injection of 30 mg strength was approximately 6% and 4% greater, respectively, as compared to when administered as two injections of 15 mg strengths.

Special Populations and Conditions

Pediatrics:  Differences in the pharmacokinetics of SOMAVERT in these populations has not been studied.

Geriatrics:  Differences in the pharmacokinetics of SOMAVERT in these populations has not been studied.

Gender:  No gender effect on the pharmacokinetics of SOMAVERT was found in a population pharmacokinetic analysis.

Race:  Differences in the pharmacokinetics of SOMAVERT in these populations has not been studied.

Hepatic/Renal Insufficiency:  No pharmacokinetic studies have been conducted in patients with renal insufficiency or hepatic insufficiency.

Storage And Stability

  • The 30 day packages contain 30 diluent pre-filled syringes and 30 vials of SOMAVERT powder (The 30 vials are supplied within 3 smaller boxes (10 vials per small box)).
  • The 1 day package contain either:
    • One pre-filled syringe and one vial of SOMAVERT powder.
      or
    • One diluent vial and one vial of SOMAVERT powder

Prior to reconstitution, SOMAVERT (pegvisomant for injection) should be stored as follows:

  • 30 day packages
    • 30 Pre-filled syringes:
      • If room temperature is below 30°C, the pre-filled syringes may be stored at room temperature (below 30°C);
      • If room temperature is above 30°C, the pre-filled syringes should be stored in a refrigerator (2ºC - 8°C). Protect from freezing.
  • 30 Vials
    • Store all 3 boxes of vials of SOMAVERT powder in a refrigerator (at 2 to 8 ºC). Protect the vials from light. Protect from freezing.
  • One day packages
    • Store the entire package in the refrigerator (at 2 to 8ºC). Protect from freezing. Protect the vials from light.
    • Pre-filled syringe:
      • If room temperature is below 30°C, only the diluent pre-filled syringe may be stored at room temperature (below 30°C).
      • If room temperature is above 30°C, the diluent pre-filled syringe should be stored in a refrigerator (2ºC - 8°C). Protect from freezing.

Reconstituted Solutions

SOMAVERT should be administered within three hours of reconstitution. Only one dose should be administered from each vial.

Dosage Forms, Composition And Packaging

Availability of Dosage Forms

SOMAVERT (pegvisomant for injection) is available in single-dose vial in the following 5 strengths, in packages that also include vials with 8 mL of Sterile Water for Injection, Ph. Eur. or with pre-filled syringes with 1 mL of Sterile Water for Injection, Ph. Eur. Pack size of 1 or 30.

SOMAVERT 10 mg, 15 mg, 20 mg, 25 mg, 30 mg are all available in the following presentations:

  • Package of 1 vial of SOMAVERT powder with 1 diluent pre-filled syringe
  • Packages of 30 vials of SOMAVERT powder with 30 diluent pre-filled syringes
  • Package of 1 vial of SOMAVERT powder with diluent vial

The stoppers on the vial of SOMAVERT and the vial of diluent are latex free.

Composition

SOMAVERT is supplied as a sterile, white lyophilized powder intended for subcutaneous injection after reconstitution with 1 mL of Sterile Water for Injection, Ph. Eur. It is available in single-dose vials containing 10, 15, 20, 25 and 30 mg of pegvisomant protein. The diluent (Sterile Water for Injection, Ph. Eur) is provided in a vial or in a pre-filled syringe that is included in the same package as the SOMAVERT vial. Each 10, 15 and 20 mg vial also contains 1.36 mg of glycine, 36.0 mg of mannitol, 1.04 mg of sodium phosphate dibasic anhydrous, and 0.36 mg of sodium dihydrogen phosphate, monohydrate. Each 25 mg vial also contains 1.7 mg of glycine, 45.0 mg of mannitol, 1.3 mg of sodium phosphate dibasic anhydrous, and 0.45 mg of sodium dihydrogen phosphate monohydrate. Each 30 mg vial also contains 2.04 mg of glycine, 54.0 mg of mannitol, 1.56 mg of sodium phosphate dibasic anhydrous, and 0.54 mg of sodium dihydrogen phosphate monohydrate.

 

Control #: 220426
November 30 2018

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